DNA polymerization activates RNA cleavage of a reverse transcriptase-like antiviral enzyme

• 成果类型: Article
• 署名作者: Rong, Xuejun; Xiao, Jun; Zhao, Xinyuan; Yan, Yan; Li, Jing; Chen, Yifan; Fan, Yihua; Liu, Zhichao; Cao, Yue; Cao, Fan; Cheng, Rui; Wang, Xionglue; Wang, Longfei; Zhu, Bin
• 署名单位: Huazhong University of Science & Technology; Wuhan University; Shenzhen Huazhong University of Science & Technology Research Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aef3178
• 发表日期: 2026-07-30
• 页码: eaef3178
• 关键词: protein

摘要

Defense-associated reverse transcriptases (DRTs) transcribe noncoding RNAs (ncRNAs) for antiviral defense, but the mechanisms of ncRNA-independent DRTs remain unclear. In this work, we show that a single DRT4 mediates RNA-targeting antiphage defense by integrating DNA polymerase, exonuclease, and RNA endonuclease activities. First, through an equilibrium between its DNA polymerase and exonuclease activities, DRT4 senses phage infection, as elevated deoxynucleotide triphosphate levels shift the equilibrium toward polymerase activity, thereby promoting protein-primed single-stranded DNA (ssDNA) synthesis. Second, ssDNA of sufficient length, phage DNA binding proteins, and deoxyguanosine triphosphate collectively activate an unusual RNA endonuclease activity of DRT4, excising guanosine 3 '-monophosphate from both phage and host RNA to terminate infection. These findings reveal a distinctive immune strategy combining nucleic acid synthesis and degradation, expanding the functional landscape of DRTs for new DNA- and RNA-processing technologies.